Implantable medical devices with anti-microbial and biodegradable matrices

ABSTRACT

A composite vascular graft is provided, which incorporates bioactive agents that can be controllably delivered to the implantation site to deliver therapeutic materials and/or to reduce infection of the implant. The vascular graft of the present invention includes a luminal layer of ePTFE; and a biodegradable polymer layer including a bioactive agent, such as an antimicrobial agent. The biodegradable polymer layer is posited on the external surface of the luminal ePTFE layer. The graft also includes a fabric layer, which is posited on the external surface of the biodegradable layer. The graft is particularly useful as an arterial-venous graft for hemodialysis procedures.

CROSS-REFERENCE TO RELATED U.S. APPLICATIONS

This application is a Continuation of and claims priority to U.S. Pat.application Ser. No. 10/873,338, filed Jun. 22, 2004, the entirecontents of which are hereby incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to implantable medical devices, whichinhibit or reduce bacterial growth during their use in a living body.More particularly, the present invention relates to composite vasculargrafts which incorporate bioactive agents to deliver therapeuticmaterials and/or to inhibit or reduce bacterial growth during andfollowing implantation, and which also desirably incorporate a luminallayer of ePTFE with an internodal distance of 70-90 microns to allow forintercellular communication.

BACKGROUND OF THE INVENTION

Poor glycemic control in diabetes and hypertension can lead to therequirement for hemodialysis. In order to facilitate treatment, asignificant number of patients with these disorders will have asynthetic vascular graft surgically implanted between the venous andarterial systems to allow arterial-venous (A-V) access at theimplantation type. The average time a synthetic graft will remain usefulfor A-V access is about two years. During these two years, infectionwill develop in around 20% of patients, and often leads to graftremoval. The hemodialysis access then has to be reestablished. Often,this means finding another site for A-V access and waiting a period oftime of three weeks before a normal hemodialysis schedule can beresumed. It is known that 15-30% of all dialysis patients will haveinfection of their implant as a major cause of death.

There are principally three ways in which an infection can be introducedduring A-V access set up or the hemodialysis procedure itself. Forexample, bacteria can be implanted with the A-V access device itselfduring a break in aseptic technique. Another way is through theattachment of bacteria which are already internally present onto thesurface of the device. Moreover, bacteria can be transmitted fromexternal sources, such as central venous catheters and needles. Themajor cause in infection involving A-V access PTFE grafts has been shownto be due to a break in aseptic cannulation. The port of entry forinfection is typically the puncture site or catheter.

The most common infectious agents are: staphylococcus aureus,pseudomonas aeruginosa, and staphylococcus epidermis. These agents havebeen identified in over 75% of all reported vascular infections. Bothstaphylococcus aureus and pseudomonas aeruginosa, show high virulenceand can lead to clinical signs of infection early in the post-operativeperiod (less than four months). It is this virulence that leads tosepticemia and is one main factor in the high mortality rates.Staphylococcus epidermis is described as a low virulence type ofbacterium. It is late occurring, which means it can present clinicalsigns of infection up to five years post-operative. This type ofbacterium has been shown to be responsible for up to 60% of all vasculargraft infections. Infections of this type often require total graftexcision, debridement of surrounding tissue, and revascularizationthrough an uninfected route.

Such high virulence organisms are usually introduced at the time ofimplantation. For example, some of the staphylococcus strains (includingstaphylococcus aureus) have receptors for tissue ligands such asfibrinogen molecules which are among the first deposits seen afterimplantation of a graft. This tissue ligand binding provides a way forthe bacteria to be shielded from the host immune defenses as well assystemic antibiotics. The bacteria can then produce polymers in the formof a polysaccharide that can lead to a slime layer on the outer surfaceof the graft. In this protective environment, bacterial reproductionoccurs and colonies form within the biofilm that can shed cells tosurrounding tissues (Calligaro, K. and Veith, Frank, Surgery, 1991V110-No. 5, 805-811). Infection can also originate from transectedlymphatics, from inter-arterial thrombus, or be present within thearterial wall.

There are severe complications as a result of vascular graft infections.For example, anastonomic disruption due to proteolytic enzymes that themore virulent organisms produce can lead to a degeneration of thearterial wall adjacent to the anastomosis. This can lead to apseudoaneurism which can rupture and cause hemodynamic instability. Afurther complication of a vascular graft infection can be distal stypticembolisms, which can lead to the loss of a limb, or aortoentericfistulas, which are the result of a leakage from a graft that isinfected and that leads to gastrointestinal bleeding (Greisler, H.,Infected Vascular Grafts. Maywood, Ill., 33-36).

Desirably, it would be beneficial to prevent any bacteria from adheringto the graft, or to the immediate area surrounding the graft at the timeof implantation. It would further be desirable to prevent the initialbacterial biofilm formation described above by encouraging normal tissueingrowth within the tunnel, and by protecting the implant itself fromthe biofilm formation.

Silver has been shown in vitro to inhibit bacterial growth in severalways. For example, it is known that silver can interrupt bacterialgrowth by interfering with bacterial replication through a binding ofthe microbial DNA, and also through the process of causing a denaturingand inactivation of crucial microbial metabolic enzymes by binding tothe sulfhydryl groups (Tweten, K., J. of Heart Valve Disease 1997, V6,No. 5, 554-561).

It is also known that silver causes a disruption of the cell membranesof blood platelets. This increased blood platelet disruption leads toincreased surface coverage of the implants with platelet cytoskeletalremains. This process has been shown to lead to an encouragement of theformation of a more structured (mature state) pannus around the implant.This would likely discourage the adhesion and formation of the biofilmproduced by infectious bacteria due to a faster tissue ingrowth time(Goodman, S. et al, 24^(th) Annual Meeting of the society forBiomaterials, April 1998, San Diego, Calif.; pg. 207).

It is known to incorporate antimicrobial agents into a medical device.For example, prior art discloses an ePTFE vascular graft, a substantialproportion of the interstices of which contain a coating compositionthat includes: a biomedical polyurethane; poly(lactic acid), which is abiodegradable polymer; and the anti-microbial agents, chlorhexidineacetate and pipracil. The prior art further describes an ePTFE herniapatch which is impregnated with a composition including silversulfadiazine and chlorhexidine acetate and poly(lactic acid).

Further prior art describes a medical implant wherein an antimicrobialagent penetrates the exposed surfaces of the implant and is impregnatedthroughout the material of the implant. The medical implant may be avascular graft and the material of the implant may bepolytetrafluoroethylene (PTFE). The antimicrobial agent is selected fromantibiotics, antiseptics and disinfectants.

Moreover, there is prior art that discloses that silver, which is aknown antiseptic agent, can be deposited onto the surface of a porouspolymeric substrate via silver, ion assisted beam deposition prior tofilling the pores of the porous polymeric material with an insoluble,biocompatible, biodegradable material. This prior art further disclosesthat antimicrobials can be integrated into the pores of the polymericsubstrate. The substrate may be a porous vascular graft of ePTFE.

It is known that multiple layers in grafts can be effective in providinga differential cross-section of permeability and/or porosity to achieveenhanced healing and tissue ingrowth. In addition, attempts to increasethe radial tensile and axial tear strengths of porous tubular graftsinclude placing multiple layers over one another. Prior art describingcomposite, anti-infective medical devices will now be discussed.

It is known to provide an anti-infective medical article including ahydrophilic polymer having silver chloride bulk distributed therein. Thehydrophilic polymer may be a laminate over a base polymer. Preferredhydrophilic polymers are disclosed as melt processible polyurethanes.The medical article may be a vascular graft. A disadvantage of thisgraft is that it is not formed of ePTFE, which is known to have naturalantithrombogenic properties. A further disadvantage is that thehydrophilic polyurethane matrix into which the silver salt isdistributed does not itself control the release of silver into thesurrounding body fluid and tissue at the implantation site of the graft.

Furthermore, there is prior art describing an implantable medical devicethat can include a stent structure, a layer of bioactive materialposited on one surface of the stent structure, and a porous polymericlayer for controlled release of a bioactive material which is positedover the bioactive material layer. The thickness of the porous polymericlayer is described as providing this controlled release. The medicaldevice can further include another polymeric coating layer between thestent structure and the bioactive material layer. This polymeric coatinglayer is disclosed as preferably being formed of the same polymer as theporous polymeric layer. Silver can be included as the stent base metalor as a coating on the stent base metal. Alternatively, silver can be inthe bioactive layer or can be posited on or impregnated in the surfacematrix of the porous polymeric layer. Polymers ofpolytetrafluoroethylene and bioabsorbable polymers can be used. Adisadvantage of this device is that the porous polymeric outer layerneeds to be applied without the use of solvents, catalysts, heat orother chemicals or techniques, which would otherwise degrade or damagethe bioactive agent deposited on the surface of the stent. Moreover,this graft is not designed to achieve fast tissue ingrowth within thetunnel to discourage initial bacterial biofilm formation.

Further prior art describes a vascular graft made with a porousantimicrobial fabric formed by fibers which are laid transverse to eachother, and which define pores between the fibers. The fibers may be ofePTFE. Ceramic particles are bound to the fabric material, the particlesincluding antimicrobial metal cations thereon, which may be silver ions.The ceramic particles are exteriorly exposed and may be bound to thegraft by a polymeric coating material, which may be a biodegradablepolymer. A disadvantage of this device is that the biodegradable coatinglayer does not provide sufficient tensile strength for an outer graftlayer. Moreover, this graft does not include a polymeric ePTFE tube,which has certain advantages over conventional textile prostheses. Forexample, a polymeric ePTFE tube has a microporous structure consistingof small nodes interconnected with many thin fibrils. The diameter ofthe fibrils, which depend on the processing conditions, can becontrolled to a large degree, and the resulting flexible structure hasgreater versatility. For example, it can be used in both large diameter,i.e. 6 mm or greater artificial blood vessels, as well as in graftshaving diameters of 5 mm or less.

There is a need for additional antimicrobial vascular grafts formed ofePTFE. In particular, there is a need for ePTFE multi-layered vasculargrafts which incorporate antimicrobial agents that can be controllablyreleased from biodegradable materials in the graft to suppress infectionfollowing implantation and to prevent biofilm formation. It would alsobe desirable to provide such grafts with sufficient tensile strength inthe tissue-contacting outer layer and with good cellular communicationbetween the blood and the perigraft tissue in the luminal layer.

SUMMARY OF THE INVENTION

The present invention solves a need in the art by providing a vasculargraft which can deliver one or more bioactive agents to the region of ablood vessel in a controlled fashion. In desired embodiments, thebioactive agents include an antimicrobial agent to inhibit or reduceinfection during and following the introduction of the graft to theimplantation site in the body. The inventive vascular graft is acomposite device including three separate layers. For example, theinvention provides a vascular graft including a luminal layer of ePTFE;and a biodegradable polymer layer, which includes at least one bioactiveagent. The biodegradable layer is posited on the external surface of theluminal ePTFE layer. The inventive graft further includes a fabriclayer, which is posited on the external surface of the biodegradablelayer.

The invention further provides a vascular graft including a luminallayer of ePTFE with an internodal distance (IND) of up to about 90microns and, desirably, about 70 to about 90 microns; and abiodegradable polymer layer that includes an antimicrobial agent, thebiodegradable layer being posited on the external surface of the luminallayer. This graft also includes a fabric layer posited on the externalsurface of the biodegradable layer, wherein the fabric layer is ofsufficient porosity to allow tissue ingrowth to replace thebiodegradable polymer layer upon hydrolysis thereof.

Preferably, the biodegradable polymer is hydrophilic with a swellingcapacity up to 300%. The bioactive agent(s) placed within thebiodegradable polymer of the medial layer are controllably released fromthe medial layer to the blood and surrounding tissue at the implantationsite. In particular, the rate of elution of the bioactive agent iscontrolled by the rate of hydrolysis of a biodegradable polymer.Desirably, the bioactive agent is a silver agent. The silver preventsbacteria from adhering to the graft, or to the area surrounding thegraft at the time of implantation and prevents initial bacterial biofilmformation by encouraging tissue ingrowth within the tunnel, and byprotecting the implant itself from biofilm formation.

The outer tissue-contacting fabric layer adds tensile strength to thegraft and is of a porosity which allows sufficient tissue ingrowth toreplace the structure of the hydrolyzed biodegradable layer. The fabriclayer further serves to encourage tissue growth within the outersurfaces of the graft, which discourages biofilm formation around thegraft.

The IND of 70 to 90 microns in the luminal ePTFE layer allows forcellular communication between the blood and the perigraft tissue. Italso encourages normal tissue ingrowth within the tunnel to discouragebiofilm formation.

The present invention also provides a method of making a vascular graftfor controllable delivery of a bioactive agent associated therewith to asite of implantation of the graft. The method includes the followingsteps: providing a luminal layer of ePTFE; positing a biodegradablepolymer layer including a bioactive agent on the external side of theluminal layer; and positing a fabric layer on the external surface ofthe biodegradable layer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic longitudinal cross-sectional representation of anembodiment of the vascular graft of the present invention.

FIG. 2 is a perspective view of a tubular vascular graft according tothe present invention.

FIG. 3 is a cross-sectional showing of an embodiment of a stent/graftcomposite of the present invention.

FIG. 4 is a photomicrograph showing a longitudinally expanded ePTFEstructure.

FIG. 5 is a perspective view of a fabric layer useful in the graft ofthe present invention.

FIG. 6 is a schematic showing of a conventional weave pattern useful forthe fabric layer of the graft of the present invention.

FIG. 7 is a side elevation view of a braided fabric layer useful in thegraft of the present invention.

FIGS. 7A-7C are schematic showings of various types of braids that canbe used in the braided fabric layer of FIG. 7. FIG. 7A depicts a diamondbraid, FIG. 7B depicts a regular braid and FIG. 7C depicts a Herculesbraid.

FIG. 8 is a side elevation view of a knitted fabric layer useful in thegraft of the present invention.

FIG. 8A is an enlarged detail of FIG. 8.

DETAILED DESCRIPTION OF THE INVENTION

In preferred embodiments of the present invention, the implantablecomposite device is a multi-layered tubular structure which isparticularly suited for use as an arterial-venous (AV) graft. Theprosthesis preferably includes at least one extrudedpolytetrafluoroethylene (PTFE) tube. PTFE exhibits superiorbiocompatibility and is suitable for vascular applications as the resultof its low thrombogenicity. Furthermore, the prosthesis includes abiodegradable polymeric material which is preferably applied as acoating layer to the ePTFE tube, and which is designed to regulatedelivery of a bioactive agent associated therewith to the site ofimplantation. In a desired embodiment, the bioactive agent is anantimicrobial agent, such as a silver agent. In particular, the rate ofelution of the silver agent is controlled by the rate of hydrolysis ofthe biodegradable polymer. The prosthesis preferably also includes athird tube of fabric that provides tensile strength to the graft andthat has a porosity sufficient to permit a sufficient tissue ingrowth toreplace the polymer structure of the biodegradable layer followinghydrolysis.

FIG. 1 shows vascular graft 10 of the present invention. As noted above,the present invention takes the preferred embodiment of a compositetubular graft, wherein the layers are shown in FIG. 1, which representthe tubular members forming the composite structure. However, it may beappreciated that the present invention also contemplates otherimplantable multi-layer prosthetic structures such as vascular patches,blood filters, film wraps for implantable devices such as stents, herniarepair fabrics and plugs and other such devices where such structuresmay be employed. As shown in FIG. 1, the composite device 10 of thepresent invention includes a luminal ePTFE layer 12 and a biodegradablelayer 14 overlaying the luminal layer 12. Biodegradable layer 14 permitscontrolled delivery of bioactive agents 16 associated with layer 14therethrough. Device 10 of the present invention further includes atextile fabric layer 18, which provides radial tensile strength at theoutermost tube and permits tissue ingrowth.

Referring now to FIG. 2, a preferred embodiment of a composite tubulargraft of the present invention is shown, wherein the layers shown inFIG. 1 represent the tubular members in FIG. 2 forming the compositestructure. Device 20 includes an inner ePTFE tubular member 22 and amedial biodegradable coating layer 24 disposed coaxially thereover.Biodegradable layer 24 includes a bioactive agent 26 which is preferablydistributed substantially evenly throughout the bulk of thebiodegradable matrix of layer 24. An outer tubular textile fabric member28 is disposed coaxially over biodegradable layer 24. As will bedescribed in further detail below, virtually any textile constructioncan be used for the fabric layer 28, including weaves, knits, braids,filament windings, spun fibers and the like. Any weave pattern in theart, including, simple weaves, basket weaves, twill weaves, velourweaves and the like may be used. The weave pattern shown in FIG. 2includes warp yarns 28 a running along the longitudinal length (L) ofthe graft and fill yarns 28 b running around the circumference (C) ofthe graft, the fill yarns being at approximately 90 degrees to oneanother with fabrics flowing from the machine in the warp direction. Acentral lumen 29 extends throughout the tubular composite graft 20defined further by the inner wall 22 a of luminal tube 22, which permitsthe passage of blood through graft 20 once the graft is properlyimplanted in the vascular system.

It is well within the contemplation of the present invention that astent can be interposed between the layers of the graft of the presentinvention. With reference to FIG. 3, a stent/graft composite device 30of the present invention is shown. Device 30 includes inner ePTFEtubular member 22 and medial, biodegradable layer 24 disposed coaxiallythereover. As described above, biodegradable layer 24 includes abioactive agent 26, such as a silver agent, which can be controllablyreleased from biodegradable layer 24. This controllable release isdependent on the rate of hydrolysis of the bonds within biodegradablelayer 24. Composite device 30 further includes fabric tubular member 28which is disposed coaxially over biodegradable layer 24. Central lumen29 extends throughout tubular composite graft 30. An expandable stent 32may be interposed between inner ePTFE tubular member 22 andbiodegradable layer 24. Stent 32, which may be associated with the graftof the present invention, is used for increased support of the bloodvessel and increased blood flow through the area of implantation. It isnoted that increased radial tensile strength at the outer tubular fabricmember 28 enables the graft to support, for example, radial expansion ofstent 32, when present.

In order to facilitate hemodialysis treatment, a significant number ofpatients suffering from hypertension or poor glycemic control indiabetes will have a synthetic vascular graft surgically implantedbetween the venous and arterial systems. Typically, these grafts becomeoccluded over time. In these instances, a covered stent across thevenous anastomotic site in patients with significant stenosis may aid inprolonging the patency of these grafts, which would avoid painful andtypically expensive surgical revisions. For these reasons, it is wellwithin the contemplation of the present invention that a stent coveredwith or incorporated within the vascular graft of the present inventionmay be useful for AV access.

As noted above, in one aspect of the present invention, composite device10, which in desired embodiments is an AV graft, includes an ePTFEluminal layer 12 depicted in FIG. 1. PTFE exhibits superiorbiocompatibility and low thrombogenicity, which makes it particularlyuseful as vascular graft material. Desirably, the ePTFE layer is atubular structure 22, as depicted in FIG. 2. The ePTFE material has afibrous state which is defined by interspaced nodes interconnected byelongated fibrils. The space between the node surfaces that is spannedby the fibrils is defined as the internodal distance. In the presentinvention, the internodal distance in the luminal ePTFE layer isdesirably greater than 40 microns, and in particular, about 70 to about90 microns. When the term “expanded” is used to describe PTFE, i.e.ePTFE, it is intended to describe PTFE which has been stretched, inaccordance with techniques which increase the internodal distance andconcomitantly porosity. The stretching may be done uni-axially,bi-axially, or multi-axially. The nodes are stretched apart by thestretched fibrils in the direction of the expansion.

FIG. 4 is a photomicrograph of a traditionally longitudinally expandedePTFE tubular structure 40. The tube has been stretched in thelongitudinal direction shown by directional arrow 42, leaving the nodescircumferentially oriented in circumferential direction shown by thedirectional arrow 44. The fibrils 46 are shown as being uniformlyoriented in the longitudinal direction shown by directional arrow 42.Nodes 48 are shown are oriented in circumferential direction 44. Methodsof making conventional longitudinally expanded ePTFE are well known inthe art.

It is further contemplated that the ePTFE may be a physically modifiedePTFE tubular structure having enhanced axial elongation and radialexpansion properties of up to 600% by linear dimension. The physicallymodified ePTFE tubular structure is able to be elongated or expanded andthen returned to its original state without an elastic force existingtherewithin. Additional details of physically-modified ePTFE and methodsfor making the same can be found in commonly assigned Application Title“ePTFE Graft With Axial Elongation Properties”, assigned U.S.application Ser. No. 09/898,418, filed on Jul. 3, 2001, published onJan. 9, 2003 as U.S. Application Publication No. 2003-0009210A1, thecontents of which are incorporated by reference herein in its entirety.

A further aspect of the composite device of the present inventionrelates to the biodegradable, medial layer shown as layer 14 in FIG. 1.The biodegradable layer may be comprised of natural, modified natural orsynthetic polymers, copolymers, block polymers, as well as combinationsthereof. Preferably, the biodegradable polymer is hydrophilic with aswelling capacity up to 300%. It is noted that a polymer is generallynamed based on the monomer it is synthesized from. Examples of suitablebiodegradable polymers or polymer classes include fibrin, collagen,elastin, celluloses, gelatin, vitronectin, fibronectin, laminin,reconstituted basement membrane matrices, starches, dextrans, alginates,hyaluronic acid, poly(lactic acid), poly(glycolic acid), polypeptides,glycosaminoglycans, their derivatives and mixtures thereof. For bothglycolic acid and lactic acid, an intermediate cyclic dimer is typicallyprepared and purified, prior to polymerization. These intermediatedimers are called glycolide and lactide, respectively.

Other useful biodegradable polymers or polymer classes include thefollowing: polydioxanones, polyoxalates, poly(.alpha.-esters),polyanhydrides, polyacetates, polycaprolactones, poly(orthoesters),polyamino acids, polyamides and mixtures and copolymers thereof.

Additional useful biodegradable polymers include, stereopolymers of L-and D-lactic acid, copolymers of bis(p-carboxyphenoxy) propane acid andsebacic acid, sebacic acid copolymers, copolymers of caprolactone,poly(lactic acid)/poly(glycolic acid)/polyethyleneglycol copolymers,copolymers of polyurethane and (poly(lactic acid), copolymers ofpolyurethane and poly(lactic acid), copolymers of .alpha.-amino acids,copolymers of .alpha.-amino acids and caproic acid, copolymers of.alpha.-benzyl glutamate and polyethylene glycol, copolymers ofsuccinate and poly(glycols), polyphosphazene, polyhydroxy-alkanoates andmixtures thereof. Binary and ternary systems are contemplated.

Other specific biodegradable polymers which are useful include thosemarketed under the Biodel and Medisorb trademarks. The Biodel materialsrepresent a family of various polyanhydrides which differ chemically.The Medisorb materials are marketed by the Dupont Company of Wilmington,Del. and are generically identified as a “lactide/glycolide co-polymer”containing “propanoic acid, 2-hydroxy-polymer with hydroxy-polymer withhydroxyacetic acid.” Four such polymers include lactide/glycolide 100 L,believed to be 100% lactide having a melting point within the range of338°-347° F. (170°-175° C.); lactide/glycolide 100 L, believed to be100% glycolide having a melting point within the range of 437°-455° F.(225°-235° C.); lactide/glycolide 85/15, believed to be 85% lactide and15% glycolide with a melting point within the range of 338°-347° F.(170°-175° C.); and lactide/glycolide 50/50, believed to be a copolymerof 50% lactide and 50% glycolide with a melting point within the rangeof 338°-347° F. (170°-175° C.).

In one desirable aspect of the invention, the polymer used to form thebiodegradable layer is a hydrogel. More desirably, the hydrogel isproduced from a synthetic polymeric material. Such synthetic polymerscan be tailored to a range of properties and predictable lot-to-lotuniformity, and represent a reliable source of material and onegenerally free from concerns of immunogenicity. In general, hydrogelsare polymeric materials that can absorb more than 20% of their weight inwater while maintaining a distinct three-dimensional structure. Thisdefinition includes dry polymers that will swell in aqueousenvironments, as well as to water-swollen materials. A host ofhydrophilic polymers can be cross-linked to produce hydrogels, whetherthe polymer is of biological origin, semi-synthetic, or whollysynthetic. Hydrogels can be grafted, bonded or otherwise affixed ontosubstrate materials, such as ePTFE. Properties that make hydrogelsvaluable in drug delivery applications include the equilibrium swellingdegree, sorption kinetics, solute permeability, and their in vivoperformance characteristics. Permeability to various solutes, includingsilver agents, depends in part upon the swelling degree or water contentand the rate of biodegradation. Since the mechanical strength of a geldeclines in direct proportion to the swelling degree, the hydrogel canbe attached to the ePTFE luminal layer so that the composite systemenhances mechanical strength. A preferred hydrogel for use in thepresent invention is a water insoluble copolymer having a hydrophilicregion, at least two functional groups that will allow for cross-linkingof the polymer chains, and a bioresorbable hydrophobic region.

In general, a suitable biodegradable polymer for use in thebiodegradable medial layer of the composite device of the presentinvention is desirably configured so that it has mechanical propertiesthat match the application, remaining sufficiently intact until thesurrounding tissue has in-grown and healed, does not invoke aninflammatory or toxic response, is metabolized in the body afterfulfilling its purpose, leaving no trace, is easily processible into thefinal product formed, demonstrates acceptable shelf-life, and is easilysterilized.

Factors affecting the mechanical performance of in vivo biodegradablepolymers are well known to the polymer scientist, and include monomerselection, initial process conditions, and the presence of additives.Biodegradation has been accomplished by synthesizing polymers that haveunstable linkages in the backbone, or linkages that can be safelyoxidized or hydrolyzed in the body. The most common chemical functionalgroups having this characteristic are ethers, esters, anhydrides,orthoesters and amides. It is noted that the biodegradable layer neednot be comprised entirely of the biodegradable material.

As described above, the biodegradable layer can include an antimicrobialagent, such as a silver agent. Silver has been shown to possessantimicrobial activity and is generally present in the devices of thepresent invention in amounts sufficient to provide antimicrobialeffects. In preferred embodiments, the silver agent comprises silvermetal ions. These silver ions are believed to exert their effects bydisrupting respiration and electron transport systems upon absorptioninto bacterial or fungal cells. Antimicrobial silver ions are useful forin vivo use because they are not substantially absorbed into the body,and typically pose no hazard to the body.

In one aspect of the invention, the silver metal ion can be selectedfrom the following: silver iodate, silver iodide, silver nitrate, andsilver oxide. The silver metal ion is desirably present in the range offrom about 0.5% to about 2 wt. % of a hydrogel in the biodegradablelayer.

The bioactive agent (e.g., a silver agent) is desirably evenlydistributed throughout the bulk of the biodegradable layer and iscontrollably released from the biodegradable layer to the site ofimplantation of the graft by hydrolysis of chemical bonds in thebiodegradable polymer.

A solution of biodegradable material that includes a monomer (or anintermediate cyclic dimer) on which the biodegradable polymer is basedcan be applied as a coating to the external side of the ePTFE luminallayer. This can be accomplished by such means as dipping, spraying,painting, etc. A silver agent or other bioactive agent can be blendedinto the wet or fluid biodegradable material to form a coating mixturewhich is then applied to the luminal layer by a spraying process, forexample. Alternatively, a silver agent or other bioactive agent may beapplied in powdered form to wet or fluid biodegradable material afterthe biodegradable material has been applied as a coat to the luminallayer, but before it solidifies.

As used herein, “solidified” means that the biodegradable material isprecipitated out to solid form. The biodegradable material is desirablycross-linked to accomplish solidification. Alternatively, thissolidification can be accomplished by other standard chemical reactionsthat are compatible with the present invention.

In preparing the biodegradable medial layer, a solution or fluid of abiocompatible, biodegradable material can be formed for application tothe external surface of the ePTFE luminal layer. For example,extracellular matrix proteins which are used in fluid/solution may besoluble. However some materials may be difficult to dissolve in water.Collagen, for example, is considered insoluble in water, as is gelatinat ambient temperature. To overcome such difficulties, collagen orgelatin may preferably formed at an acidic pH, i.e. at a pH less than 7and, preferably, at a pH of about 2 to about 4. The temperature range atwhich such fluid/solutions are formed is between about 4° C. to about40° C., and preferably about 30° C.-35° C.

In situations where the bioactive agent is insoluble in the wet or fluidbiodegradable polymer material, the agent may be finely subdivided as bygrinding with a mortar and pestle. For example, a silver agent can bemicronized to yield a product wherein some or all particles are the sizeof about 5 microns or less. The finely subdivided silver agent can thenbe distributed desirably substantially evenly throughout the bulk of thewet or fluid biodegradable layer before cross-linking or cure solidifiesthe layer.

It is well within the contemplation of the present invention that thebiodegradable layer can be combined with various carrier, drug,prognostic, diagnostic, or therapeutic materials. For example, thebiodegradable layer can be combined with any of the following bioactiveagents: antimicrobial agents (such as silver agents, chlorhexidine,triclosan, iodine, and benzalkonium chloride); anti-thrombogenic agents,such as heparin, heparin derivatives, urokinase, and PPack(dextrophenylalanine proline, arginine, chloromethylketone);anti-proliferative agents (such as enoxaprin, angiopeptin, or monoclonalantibodies capable of blocking smooth muscle cell proliferation,hirudin, and acetylsalicylic acid); anti-inflammatory agents, such asdexamethasone, prednisolone, corticosterone, budesonide, estrogen,sulfasalazine, and mesalamine);anti-neoplastics/anti-proliferative/anti-miotic agents (such aspaclitaxel, 5-flurouracil, cisplatin, vinblastine, vincristine,epothilones, endostatin, angiostatin and thymidine kinase inhibitors);anesthetic agents (such as lidocaine, bupivacaine, and ropivacaine);anti-coagulants (such as D-Phe-Pro-Arg chloromethyl keton, an RGDpeptide-containing compound, heparin, antithrombin compounds, plateletreceptor antagonists, anti-thrombin antibodies, anti-platelet receptorantibodies, aspirin, prostaglandin inhibitors, platelet inhibitors andtick anti-platelet peptides); vascular cell growth promoters (such asgrowth factor inhibitors, growth factor receptor antagonists,transcriptional activators, and translational promoters); vascular cellgrowth inhibitors (such as growth factor inhibitors, growth factorreceptor antagonists, transcriptional repressors, translationalrepressors, replication inhibitors, inhibitory antibodies, antibodiesdirected against growth factors, bi-functional molecules consisting of agrowth factor and a cytotoxin, bi-functional molecules consisting of anantibody and a cytotoxin); cholesterol-lowering agents; vasodilatingagents; and agents which interfere with andogenous or vascoactivemechanisms. In addition, cells which are able to survive within the bodyand are dispersed within the biodegradable layer may be therapeuticallyuseful. These cells themselves may be therapeutically useful or they maybe selected or engineered to produce and release therapeutically usefulcompositions.

In other embodiments, bioactive agents associated with the compositedevice of the present invention may be genetic agents. Examples ofgenetic agents include DNA, anti-sense DNA, and anti-sense RNA. DNAencoding one of the following may be particularly useful in associationwith an implantable device according to the present invention: (a) tRNAor RRNA to replace defective or deficient endogenous molecules; (b)angiogenic factors including growth factors such as acidic and basicfibroblast growth factors, vascular endothelial growth factor, epidermalgrowth factor, transforming growth factor .alpha. and .beta.,platelet-derived endothelial growth factor, platelet-derived growthfactor, tumor necrosis factor .alpha., hepatocyte growth factor andinsulin-like growth factor; (c) cell cycle inhibitors; (d) thymidinekinase and other agents useful for interfering with cell proliferation;and (e) the family of bone morphogenic proteins. Moreover, DNA encodingmolecules capable of inducing an upstream or downstream effect of a bonemorphogenic protein may be useful.

In another aspect of the present invention, composite device 10 in FIG.1 includes fabric layer 18, which is exposed on the external surface ofbiodegradable layer 14. The fabric layer is added for tensile strengthand is of sufficient porosity to allow sufficient tissue ingrowth toreplace the structure of the biodegradable polymer as it is hydrolyzed.Any type of textile products can be used as yarns for a fabric layer. Ofparticular usefulness in forming a fabric layer for the composite deviceof the present invention are synthetic materials such as syntheticpolymers. Synthetic yarns suitable for use in the fabric layer include,but are not limited to, polyesters, including PET polyesters,polypropylenes, polyethylenes, polyurethanes andpolytetrafluoroethylenes-. The yarns may be of the mono-filament,multi-filament, spun-type or combinations thereof. The yarns may also beflat, twisted or textured, and may have high, low or moderate shrinkageproperties or combinations thereof. Additionally, the yarn type and yarndenier can be selected to meet specific properties desired for theprosthesis, such as porosity and flexibility. The yarn denier representsthe linear density of the yarn (number of grams mass divided by 9,000meters of length). Thus, a yarn with a small denier would correspond toa very fine yarn, whereas a yarn with a large denier, e.g., 1,000, wouldcorrespond to a heavy yarn. The yarns used for the fabric layer of thedevice of the present invention may have a denier from about 20 to about200, preferably from about 30 to about 100. Desirably, the yarns arepolyester, such as polyethylene terephthalate (PET). Polyester iscapable of shrinking during a heat-set process, which allows it to beheat-set on a mandrel to form a generally circular shape.

After forming the fabric layer of the present invention, it isoptionally cleaned or scoured in a basic solution of warm water. Thetextile is then rinsed to remove any remaining detergent, and is thencompacted or shrunk to reduce and control in part the porosity of thefabric layer. Porosity of a textile material is measured on theWesolowski scale and by the procedure of Wesolowski. In this test, afabric test piece is clamped flatwise and subjected to a pressure headof about 120 mm of mercury. Readings are obtained which express thenumber of mm of water permeating per minute through each squarecentimeter of fabric. A zero reading represents absolute waterimpermeability and a value of about 20,000 represents approximate freeflow of fluid.

The porosity of the fabric layer is often about 7,000 to about 15,000 onthe Wesolowski scale. A more desirable porosity is from about 30 toabout 5,000 on the Wesolowski scale. Most desirably, the porosity isfrom about 5,000 to about 17,000 on this scale to permit tissueingrowth, while retaining tensile strength in the outer layer. Thefabric layer may be compacted or shrunk in the wale direction to obtainthe desired porosity. A solution of organic component, such ashexafluoroisopropanol or trichloroacetic acid, and a halogenatedaliphatic hydrocarbon, such as methylene chloride, can be used tocompact the textile graft by immersing it into the solution for up to 30minutes at temperatures from about 15° C. to about 160° C.

Yarns of the fabric layer may be one ply or multi-ply yarns. Multi-plyyarns may be desirable to impart certain properties onto the drawn yarn,such as higher tensile strengths for the outer fabric layer.

It is well within the contemplation of the present invention that theyarns of the fabric layer can have virtually any textile construction,including weaves, knits, braids, filament windings, spun fibers and thelike. For example, with reference to FIGS. 5 and 6, a woven tubularprosthesis is shown. Any known weave pattern for the fabric layer may beused, including simple weaves, basket weaves, twill weaves, velourweaves and the like may be used. The weave pattern includes warp yarns 2running along the longitudinal length (L) of the woven product and fillyarns 3 running around the circumference (C) of the woven product. Thewarp and fill yarns are at approximately 90 degrees to one another withfabric flowing from the machine in the warp direction.

Braiding may also be used, as shown for example in FIGS. 7 and 7A-7C.Braiding of yarns includes the interlacing of a two yarn systems, suchas the pass of the yarns are diagonal to the fabric delivery direction,forming either flat or tubular structure. Useful braids include aninterlocking three-dimensional braid and a solid three-dimensionalbraid. A multi-layered braided structure is defined as a structureformed by braiding wherein the structure has a plurality of distinct anddiscrete layers. These layers may be bound by interlocking yarns or byadhesive laminates, sewing or the like.

In a preferred embodiment, a knitted stretch overlay is used as thefabric layer as shown in FIGS. 8 and 8A. Knitting involves theinterlooping of one yarn system into vertical columns and horizontalrows of loops called wales and courses, respectively, the fabric comingout of the machine in the wale direction.

A filament wound prosthesis, such as that described in U.S. Pat. No.5,116,360, may also be used where fibers are drawn directly onto arotating mandrel to form a fabric layer that is wrapped with the strandsin both directions to provide a bi-axial reinforcement. In particular,as the distributor or spinnerette reciprocates along the mandrel,non-woven strands are layered on top of each other to form a porousnon-woven network of criss-crossing strands. Methods for forming afilament wound prosthesis are described in U.S. Pat. No. 4,475,972.

Generally, tubular fabric layers are manufactured in a single long tubeand cut to a pre-determined length. To cut the fabric layer, a laserwould be desirably used, which cuts and fuses the ends simultaneously.The fabric layer is cleaned, desirably with sodium dodecyl sulfate andthen rinsed with deionized water. The fabric layer can then be placedover the biodegradable layer and heat set to precisely set the diameterand to remove any creases or wrinkles. Typically, heat setting iscarried out at the temperature range from about 125° C. to about 225° C.using a convection oven for a time of 20 minutes. Any known means forheating may be used. Any means of affixing the fabric layer to thebiodegradable layer may be used including, but not limited to,cross-linking a biodegradable polymer in the biodegradable layer so asto bond the graft layers together.

Specifically, the composite device of the present invention may beformed by expanding a thin wall PTFE inner luminal tube at a relativelyhigh degree of elongation, on the order of approximately between 400%and 2,000% elongation and preferably from about between 700% and 900%.The inner luminal tube is desirably expanded over a cylindrical mandrel,such as a stainless steel mandrel at a temperature of between roomtemperature and 640° F., preferably about 500° F. The luminal tube ispreferably, but not necessarily fully sintered after expansion.Sintering is typically accomplished at a temperature of between 640° F.and 800° F., preferably at about 660° F. and for a time of between about5 minutes to 30 minutes, preferably about 15 minutes. The resultingluminal tube formed by this method desirably exhibits an IND of greaterthan 40 microns, and in particular between 40 and 100 microns, mostdesirably between 70 to about 90 microns, spanned by a moderate numberof fibrils. Such a microporous structure is sufficiently large so as topromote enhanced cell endothelization once blood flow is establishedthrough the graft. Such cell endothelization enhances the long-termpatency of the graft.

The combination of the luminal ePTFE tube over the mandrel is thenemployed as a substrate over which the biodegradable layer can bedisposed. In particular, the biodegradable layer is disposed on theexternal surface of the luminal ePTFE tube. In one desired embodiment,the biodegradable layer is comprised of a synthetic hydrogel polymerthat can be crosslinked so as to solidify. In one embodiment, wet orfluid biodegradable material may be directly applied as a coating on theoutside surface of the luminal layer by such methods as dipping,spraying or painting. A powder form of the bioactive agent can beapplied to the biodegradable coating on the external surface of theluminal layer while it is still wet, or, alternatively, can be mixedwith the biodegradable material before application to the externalsurface of the luminal layer.

As described above, the device according to the present inventionfurther includes a fabric layer. In particular, the combination of thecomposite formed between the luminal ePTFE tube and the biodegradablelayer is then employed as a substrate, over which the fabric layer canbe disposed. Useful textile constructions include weaves, knits, braids,filament windings, spun windings and combinations thereof. Preferably,the fabric layer is a knitted stretch overlay that is applied to a wetbiodegradable coating layer, such as the aforementioned synthetichydrogel polymer. After application of the textile layer to the wethydrogel polymer layer, the hydrogel can be crosslinked by such means asmicrowave or chemical crosslinking (e.g. via formaldehyde vapor) to bondthe graft layers together.

The following examples serve to provide further appreciation of theinvention, but are not meant in any way to restrict the scope of theinvention.

EXAMPLES Example 1

The composite device of the present invention is formed by expanding athin wall PTFE inner luminal tube at a degree of elongation on the orderof 600-900%. The inner luminal tube is expanded over a cylindricalstainless steel mandrel at a temperature of 500° F. The luminal tube isfully sintered after expansion at a temperature of 660° F. for 15minutes. The resulting luminal tube formed by this method exhibits anIND of greater than 40 microns, and in particular between 70 and 90microns, and is spanned by a moderate number of fibrils.

The combination of the luminal ePTFE tube over the mandrel is thenemployed as a substrate over which the biodegradable layer is disposed.In particular, the biodegradable layer is formed of a synthetic hydrogelpolymer. The hydrogel is a water-insoluble copolymer having ahydrophilic region, at least two functional groups that will allow forcross-linking of the polymer chains and a bioresorbable hydrophobicregion. Silver iodate is blended into wet hydrogel material to form amixture which is sprayed onto the external surface of the luminal ePTFEtube.

The combination of the composite formed between the luminal ePTFE tubeand the wet biodegradable coating layer is then employed as a substrateover which the fabric layer is disposed. A knitted fabric layer formedof polyester yarns capable of shrinking during a heat-set process isused. This allows the fabric layer to be heat-set on the mandrel to forma generally cylindrical shape and removes creases or wrinkles. The yarnsused for the fabric layer have a denier from about 30 to about 100. Inparticular, the yarns are polyethylene terephthalate (PET). Afterknitting the fabric layer, it is cleaned and scoured in a basic solutionof warm water. After rinsing to remove any remaining detergent, thefabric layer is compacted or shrunk to reduce and control the porosityof the fabric layer. The porosity of the knitted material is about 5,000to about 17,000 when measured on the Wesolowski scale and by theprocedure of Wesolowski. This porosity permits tissue ingrowth, whileretaining tensile strength in the outer layer. In order to compact orshrink the fabric layer in the wale direction to obtain this desiredporosity, a solution of hexafluoroisopropanol and methylene chloride isused to compact the textile layer by immersing it into the solution for30 minutes at a temperature from about 15° C. to about 160° C. After thefabric layer has been applied to the biodegradable coating layer, thecomposite structure is placed in a microwave so as to crosslink thehydrogel. The crosslinking of the hydrogel serves to bond the graftlayers together.

1. A vascular graft comprising: a luminal layer of ePTFE, the luminallayer is at least partially sintered; a biodegradable polymer layercomprising a bioactive agent and at least one biodegradable polymer, theat least one biodegradable polymer comprising a hydrophilic region, atleast two functional groups that will allow for cross-linking of thepolymer, and a bioresorbable hydrophobic region, the bioactive agentcontrollably releases from the biodegradable polymer layer to the siteof implantation of the graft, the biodegradable polymer layer beingposited on the external surface of the luminal layer; and a fabric layerposited on the external surface of said biodegradable polymer layer;wherein said at least partially sintered luminal layer and said heat-setfabric layer are bonded together via cross-linking of said biodegradablepolymer layer.
 2. The vascular graft of claim 1 wherein the bioactiveagent is distributed throughout the biodegradable layer.
 3. The vasculargraft of claim 1 further comprising an implantable prosthetic stentinterposed between the luminal layer and the biodegradable polymerlayer.
 4. The vascular graft of claim 1 wherein the fabric layercomprises a textile construction selected from the group consisting ofweaves, knits, braids, filament windings, spun fibers and combinationsthereof.
 5. The vascular graft of claim 1 wherein said fabric layercomprises a knitted textile construction.
 6. The vascular graft of claim1 wherein said fabric comprises a heat-set diameter.
 7. The vasculargraft of claim 1 wherein said fabric has a porosity from about 5,000 toabout 17,000 on the Wesolowski scale.
 8. The vascular graft of claim 1wherein said bioactive agent is controllably released from saidbiodegradable layer to the site of implantation of said graft byhydrolysis of chemical bonds in said biodegradable polymer.
 9. Thevascular graft of claim 1 wherein the biodegradable polymer compriseschemical functional groups, the chemical functional groups comprise atleast one member selected from the group consisting of ethers, esters,anhydrides, orthoesters and amides.
 10. The vascular graft of claim 1wherein said polymer is selected from the group consisting of fibrin,collagen, elastin, celluloses, gelatin, vitronectin, fibronectin,laminin, reconstituted basement membrane matrices, starches, dextrans,alginates, hyaluronic acid, poly(lactic acid), poly(glycolic acid),polypeptides, glycosaminoglycans, their derivatives, and mixturesthereof.
 11. The vascular graft of claim 1 wherein said polymer isselected from the group consisting of polydioxanones, polyoxalates,poly(alpha-esters), polyanhydrides, polyacetates, polycaprolactones,poly(orthoesters), polyamino acids, polyamides and copolymers thereof,and mixtures thereof.
 12. The vascular graft of claim 1 wherein saidpolymer comprises a member selected from the group consisting ofstereopolymers of L- and D-lactic acid, copolymers ofbis(p-carboxyphenoxy) propane acid and sebacic acid, sebacic acidcopolymers, copolymers of caprolactone, poly(lactic acid)/poly(glycolicacid)/polyethyleneglycol copolymers, copolymers of polyurethane and(poly(lactic acid), copolymers of polyurethane and poly(lactic acid),copolymers of .alpha.-amino acids, copolymers of .alpha.-amino acids andcaproic acid, copolymers of .alpha.-benzyl glutamate and polyethyleneglycol, copolymers of succinate and poly(glycols), polyphosphazene,polyhydroxy-alkanoates and mixtures thereof.
 13. The vascular graft ofclaim 1 wherein the bioactive agent is an antimicrobial agent that is anantiseptic agent.
 14. The vascular graft of claim 1 wherein saidbioactive agent is a silver agent.
 15. The vascular graft of claim 14wherein said silver agent comprises silver metal ions.
 16. The vasculargraft of claim 1 wherein said biodegradable layer comprises a hydrogel.17. The vascular graft of claim 16 wherein said silver agent comprisessilver metal ion, said silver metal ions are present in amounts of about0.5% to about 2 wt. % of the hydrogel in the biodegradable layer. 18.The vascular graft of claim 1 wherein the antimicrobial agent is anantiseptic agent selected from the group consisting of chlorohexidine,triclosan, iodine, benzalkonium chloride, and combinations thereof. 19.The vascular graft of claim 1, wherein said fabric layer is formed fromsynthetic yarns selected from the group consisting of polyesters, PETpolyesters, polypropylenes, polyethylenes, polyurethanes,polytetrafluoroethylenes and combinations thereof.
 20. The vasculargraft of claim 1 wherein the fabric layer is formed of syntheticpolyester yarns.